The present invention relates to novel benzene compounds. In detail, the present invention relates to benzene compounds useful as immunosuppressants, optically active isomers thereof and salts thereof, and pharmaceutical use thereof.
In recent years, cyclosporin is in use for suppressing rejection developed in transplanting organs. Inclusive of the compounds currently under development, the so-called immunosuppressants are expected to be useful as therapeutic agents for articular rheumatism and so on. Said cyclosporin, however, also possesses problems of side effects such as renal disorders.
Meanwhile, Japanese Patent Unexamined Publication No. 104087/1989 discloses that an immunosuppressive substance is obtained from a liquid culture of Isaria sinclairii and said substance has been confirmed to be (2S, 3R, 4R)-(E)-2-amino-3,4-dihydroxy-2-hydroxymethyl-14-oxoicosa-6-enoic acid of the formula 
disclosed in U.S. Pat. No. 3928572. In addition, Japanese Patent Unexamined Publication No. 128347/1991 states that a series of said compound has an immunosuppressive action.
Referring to Merck Index, 11th edition, it is described that 2-amino-2-methyl-1,3-propanediol (Index No. 460), 2-amino-2-ethyl-1,3-propanediol (Index No. 451) and 2-amino-2-hydroxymethyl-1,3-propanediol (also called as tromethamine, Index No. 9684) can be used as intermediates for surface-active agents and pharmaceuticals, emulsifying agent or gas adsorbents and that tromethamine is medically usable as an alkalizer. In Japanese Patent Unexamined Publication No. 416/1987, a hair dye containing 2-amino-2-(C1-C5 alkyl)-1,3-propanediol is disclosed. U.S. Pat. No. 4,910,218 and J. Med. Chem., vol.33, 2385-2393 (1990) teach 2-amino-2-(methyl or ethyl)-1,3-propanediol as a synthetic intermediate for an antitumor agent. Also, Japanese Patent Unexamined Publication No. 192962/1984 teaches that the aforementioned 2-amino-2-(C1-C5 alkyl)-1,3-propanediol or 2-amino-1,3-propanediol can be used as a stabilizer for an antigen or antibody-sensitized latex reagent. Moreover, U.S. Pat. No. 3,062,839 teaches 2-methyl- or ethyl-amino-2-(furylmethyl, phenylmethyl or phenylmethyl substituted by lower alkyl, lower alkoxy, chloro, hydroxy or unsubstituted amine)-1,3-propanediol having a tranquilizing action and J. Org. Chem., vol.25, 2057-2059 (1960) teaches 2-methylamino-2-(phenylmethyl or phenylmethyl substituted by 2-methyl, 3-methyl, 4-methyl, 4-methoxy or 4-hydroxy)-1,3-propanediol. Eur. J. Med. Chem. vol.25, 35-44 (1990) teaches a substituted ethylenediamine such as 3-(4-methoxyethoxyphenyl)-1,2-diaminopropane, 5-phenyl-1,2-diaminopentane, 6-phenyl-1,2-diaminohexane, can be used as a ligand of a platinum (II) complex having antitumor activity. Moreover, WO92/16236 teaches sphingosine derivatives useful as membrane penetration enhancer. It has not been known, however, that these compounds have immunosuppressive actions such as suppression of rejection developed in organ transplantation, and prevention and treatment of autoimmune diseases.
WO94/08943 discloses 2-amino-1,3-propanediol compounds having immunosuppressive action. Moreover, in Bioorganic and Medicinal Chemistry Letters, vol.5, No.8, 853-856 (1995), 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (hereinafter sometimes referred to as FTY720) as a novel synthetic immunosuppressant is disclosed, and in ibid., vol.5, No.8, 847-852 (1995), 2-amino-2-tetradecylpropane-1,3-diol as an immunosuppressant is disclosed.
An object of the present invention is to provide novel benzene compounds useful as pharmaceuticals, and having superior immunosuppressive action with less side effects.
Another object of the present invention is to provide pharmaceuticals containing said compounds.
The present invention is as follows.
(1) A benzene compound of the formula 
wherein W is hydrogen; a straight- or branched chain alkyl having 1 to 6 carbon atoms; a straight- or branched chain alkenyl having 2 to 6 carbon atoms; a straight- or branched chain alkynyl having 2 to 6 carbon atoms; a phenyl which may be substituted by hydroxy; R4O(CH2)n; or a straight- or branched chain C1-C6 alkyl substituted by 1 to 3 substituents selected from the group consisting of a halogen, a cycloalkyl and a phenyl which may be substituted by hydroxy;
X is hydrogen, a straight-chain alkyl having carbon atoms in the number of p or a straight-chain alkoxy having carbon atoms in the number of (pxe2x88x921), wherein the straight-chain alkyl having carbon atoms in the number of p and the straight-chain alkoxy having carbon atoms in the number of (pxe2x88x921) may have 1 to 3 substituents selected from the group consisting of an alkyl, hydroxy, an alkoxy, an acyloxy, amino, an alkylamino, an acylamino, oxo, a haloalkyl, a halogen and a phenyl which may have a substituent and wherein the phenyl which may have a substituent, may have 1 to 3 substituents selected from the group consisting of an alkyl, hydroxy, an alkoxy, an acyl, an acyloxy, amino, an alkylamino, an acylamino, a haloalkyl and a halogen;
Y is hydrogen, an alkyl, hydroxy, an alkoxy, an acyl, an acyloxy, amino, an alkylamino, an acylamino, a haloalkyl or a halogen;
Z is a single bond or a straight-chain alkylene having carbon atoms in the number of q;
p and q are the same or different and each is an integer of 1 to 20, with the proviso of 6xe2x89xa6p+qxe2x89xa623; m is 1, 2 or 3; n is 2 or 3;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl, R3 is hydrogen, an alkyl or an acyl; and R4 is hydrogen, an alkyl or an acyl,
an optically active isomer thereof and a salt thereof.
(2) The benzene compound of (1), having the formula 
wherein W1 is a straight- or branched chain alkyl having 1 to 6 carbon atoms; a straight- or branched chain alkenyl having 2 to 6 carbon atoms; a straight- or branched chain alkynyl having 2 to 6 carbon atoms; or a straight- or branched chain C1-C6 alkyl substituted by 1 to 3 substituents selected from the group consisting of a halogen, a cycloalkyl and a phenyl which may be substituted by hydroxy;
X1 is a straight-chain alkyl having 5 to 19 carbon atoms or a straight-chain alkoxy having 4 to 18 carbon atoms, wherein the straight-chain alkyl having 5 to 19 carbon atoms and the straight-chain alkoxy having 4 to 18 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino, oxo and phenyl;
Y1 is hydrogen, an alkyl, hydroxy or an alkoxy;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
and R3 is hydrogen, an alkyl or an acyl,
an optically active isomer thereof and a salt thereof.
(3) The benzene compound of (2), having the formula 
wherein W2 is a straight- or branched chain alkyl having 1 to 4 carbon atoms; a straight- or branched chain alkenyl having 2 or 3 carbon atoms; a straight- or branched chain alkynyl having 2 or 3 carbon atoms; or a straight- or branched chain C1-C3 alkyl substituted by 1 to 3 substituents selected from the group consisting of a halogen, a cycloalkyl and a phenyl which may be substituted by hydroxy;
X1 is a straight-chain alkyl having 5 to 19 carbon atoms or a straight-chain alkoxy having 4 to 18 carbon atoms, wherein the straight-chain alkyl having 5 to 19 carbon atoms and the straight-chain alkoxy having 4 to 18 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino, oxo and phenyl;
Y1 is hydrogen, an alkyl, hydroxy or an alkoxy;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
and R3 is hydrogen, an alkyl or an acyl,
an optically active isomer thereof and a salt thereof.
(4) The benzene compound of (3), having the formula 
wherein W2 is a straight- or branched chain alkyl having 1 to 4 carbon atoms; a straight- or branched chain alkenyl having 2 or 3 carbon atoms; a straight- or branched chain alkynyl having 2 or 3 carbon atoms; or a straight- or branched chain C1-C3 alkyl substituted by 1 to 3 substituents selected from the group consisting of a halogen, a cycloalkyl and a phenyl which may be substituted by hydroxy;
X1 is a straight-chain alkyl having 5 to 19 carbon atoms or a straight-chain alkoxy having 4 to 18 carbon atoms, wherein the straight-chain alkyl having 5 to 19 carbon atoms and the straight-chain alkoxy having 4 to 18 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino, oxo and phenyl;
Y2 is hydrogen, hydroxy or an alkoxy;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
and R3 is hydrogen, an alkyl or an acyl,
an optically active isomer thereof and a salt thereof.
(5) The benzene compound of (4), having the formula 
wherein W2 is a straight- or branched chain alkyl having 1 to 4 carbon atoms; a straight- or branched chain alkenyl having 2 or 3 carbon atoms; a straight- or branched chain alkynyl having 2 or 3 carbon atoms; or a straight- or branched chain C1-C3 alkyl substituted by 1 to 3 substituents selected from the group consisting of a halogen, a cycloalkyl and a phenyl which may be substituted by hydroxy;
X1 is a straight-chain alkyl having 5 to 19 carbon atoms or a straight-chain alkoxy having 4 to 18 carbon atoms, wherein the straight-chain alkyl having 5 to 19 carbon atoms and the straight-chain alkoxy having 4 to 18 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino, oxo and phenyl;
Y3 is hydrogen or an alkoxy;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
and R3 is hydrogen, an alkyl or an acyl,
an optically active isomer thereof and a salt thereof.
(6) The benzene compound of (3), having the formula 
wherein W2 is a straight- or branched chain alkyl having 1 to 4 carbon atoms; a straight- or branched chain alkenyl having 2 or 3 carbon atoms; a straight- or branched chain alkynyl having 2 or 3 carbon atoms; or a straight- or branched chain C1-C3 alkyl substituted by 1 to 3 substituents selected from the group consisting of a halogen, a cycloalkyl and a phenyl which may be substituted by hydroxy;
X1 is a straight-chain alkyl having 5 to 19 carbon atoms or a straight-chain alkoxy having 4 to 18 carbon atoms, wherein the straight-chain alkyl having 5 to 19 carbon atoms and the straight-chain alkoxy having 4 to 18 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino, oxo and phenyl;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
and R3 is hydrogen, an alkyl or an acyl,
an optically active isomer thereof and a salt thereof.
(7) The benzene compound of (6), having the formula 
wherein W2 is a straight- or branched chain alkyl having 1 to 4 carbon atoms; a straight- or branched chain alkenyl having 2 or 3 carbon atoms; a straight- or branched chain alkynyl having 2 or 3 carbon atoms, or a straight- or branched chain C1-C3 alkyl substituted by 1 to 3 substituents selected from the group consisting of a halogen, a cycloalkyl and a phenyl which may be substituted by hydroxy;
X2 is a straight-chain alkyl having 7 to 12 carbon atoms or a straight-chain alkoxy having 6 to 11 carbon atoms, wherein the straight-chain alkyl having 7 to 12 carbon atoms and the straight-chain alkoxy having 6 to 11 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino and oxo;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
and R3 is hydrogen, an alkyl or an acyl,
an optically active isomer thereof and a salt thereof.
(8) The benzene compound of (6), having the formula 
wherein W3 is a straight- or branched chain alkyl having 1 to 3 carbon atoms; a straight- or branched chain alkenyl having 2 or 3 carbon atoms; a straight- or branched chain alkynyl having 2 or 3 carbon atoms; or a straight- or branched chain C1-C3 alkyl substituted by 1 to 3 halogens;
X2 is a straight-chain alkyl having 7 to 12 carbon atoms or a straight-chain alkoxy having 6 to 11 carbon atoms, wherein the straight-chain alkyl having 7 to 12 carbon atoms and the straight-chain alkoxy having 6 to 11 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino and oxo;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
and R3 is hydrogen, an alkyl or an acyl,
an optically active isomer thereof and a salt thereof.
(9) The benzene compound of (7), having the formula 
wherein W2 is a straight- or branched chain alkyl having 1 to 4 carbon atoms; a straight- or branched chain alkenyl having 2 or 3 carbon atoms; a straight- or branched chain alkynyl having 2 or 3 carbon atoms; or a straight- or branched chain C1-C3 alkyl substituted by 1 to 3 substituents selected from the group consisting of a halogen, a cycloalkyl and a phenyl which may be substituted by hydroxy;
X2 is a straight-chain alkyl having 7 to 12 carbon atoms or a straight-chain alkoxy having 6 to 11 carbon atoms, wherein the straight-chain alkyl having 7 to 12 carbon atoms and the straight-chain alkoxy having 6 to 11 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino and oxo; and
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms,
an optically active isomer thereof and a salt thereof.
(10) The benzene compound of (8), having the formula 
wherein W3 is a straight- or branched chain alkyl having 1 to 3 carbon atoms; a straight- or branched chain alkenyl having 2 or 3 carbon atoms; a straight- or branched chain alkynyl having 2 or 3 carbon atoms; or a straight- or branched chain C1-C3 alkyl substituted by 1 to 3 halogens;
X2 is a straight-chain alkyl having 7 to 12 carbon atoms or a straight-chain alkoxy having 6 to 11 carbon atoms, wherein the straight-chain alkyl having 7 to 12 carbon atoms and the straight-chain alkoxy having 6 to 11 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino and oxo; and
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
an optically active isomer thereof and a salt thereof.
(11) The benzene compound of (10), which is selected from the group consisting of
2-amino-2-methyl-4-(4-octylphenyl)butanol,
2-amino-2-methyl-4-(4-octanoylphenyl)butanol,
2-amino-4-[4-(1-hydroxyoctyl)phenyl]-2-methylbutanol,
2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol,
(+)-2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol,
(xe2x88x92)-2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol,
2-amino-4-(4-decylphenyl)-2-methylbutanol,
2-amino-2-methyl-4-(4-nonyloxyphenyl)butanol,
2-amino-4-(4-dodecylphenyl)-2-methylbutanol,
2-amino-2-methyl-4-(4-undecyloxyphenyl)butanol,
2-amino-2-ethyl-4-(4-octylphenyl)butanol,
2-amino-2-ethyl-4-(4-octanoylphenyl)butanol,
2-amino-2-ethyl-4-[4-(1-hydroxyoctyl)phenyl]butanol,
2-amino-4-[4-(1-aminooctyl)phenyl]-2-ethylbutanol,
2-amino-2-ethyl-4-(4-heptyloxyphenyl)butanol,
2-amino-2-[2-(4-octylphenyl)ethyl]pentanol,
2-amino-2-[2-(4-octanoylphenyl)ethyl]pentanol,
2-amino-2-[2-[4-(1-hydroxyoctyl)phenyl]ethyl]pentanol,
2-amino-2-[2-[4-(1-aminooctyl)phenyl]ethyl]pentanol,
2-amino-2-[2-(4-heptyloxyphenyl)ethyl]pentanol,
(R)-2-amino-2-[2-(4-heptyloxyphenyl)ethyl]pentanol,
(S)-2-amino-2-[2-(4-heptyloxyphenyl)ethyl]pentanol,
2-amino-4-fluoro-2-[2-(4-heptyloxyphenyl)ethyl]butanol and
2-amino-2-isopropyl-4-(4-heptyloxyphenyl)butanol,
an optically active isomer thereof and a salt thereof.
(12) The benzene compound of (10), which is selected from the group consisting of
2-amino-2-methyl-4-(4-octylphenyl)butanol,
2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol,
(+)-2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol,
(xe2x88x92)-2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol,
2-amino-4-(4-decylphenyl)-2-methylbutanol,
2-amino-2-methyl-4-(4-nonyloxyphenyl)butanol,
2-amino-4-(4-dodecylphenyl)-2-methylbutanol,
2-amino-2-methyl-4-(4-undecyloxyphenyl)butanol,
2-amino-2-ethyl-4-(4-heptyloxyphenyl)butanol,
2-amino-2-[2-(4-octylphenyl)ethyl]pentanol,
2-amino-2-[2-(4-octanoylphenyl)ethyl]pentanol,
2-amino-2-[2-[4-(1-hydroxyoctyl)phenyl]ethyl]pentanol,
2-amino-2-[2-(4-heptyloxyphenyl)ethyl]pentanol,
(R)-2-amino-2-[2-(4-heptyloxyphenyl)ethyl]pentanol,
(S)-2-amino-2-[2-(4-heptyloxyphenyl)ethyl]pentanol,
2-amino-4-fluoro-2-[2-(4-heptyloxyphenyl)ethyl]butanol and
2-amino-2-isopropyl-4-(4-heptyloxyphenyl)butanol,
an optically active isomer thereof and a salt thereof.
(13) The benzene compound of (10), which is selected from the group consisting of
2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol,
2-amino-2-ethyl-4-(4-heptyloxyphenyl)butanol,
(R)-2-amino-2-[2-(4-heptyloxyphenyl)ethyl]pentanol and
2-amino-2-isopropyl-4-(4-heptyloxyphenyl)butanol,
an optically active isomer thereof and a salt thereof.
(14) The benzene compound of (3), having the formula 
wherein W2 is a straight- or branched chain alkyl having 1 to 4 carbon atoms; a straight- or branched chain alkenyl having 2 or 3 carbon atoms; a straight- or branched chain alkynyl having 2 or 3 carbon atoms; or a straight- or branched chain C1-C3 alkyl substituted by 1 to 3 substituents selected from the group consisting of a halogen, a cycloalkyl and a phenyl which may be substituted by hydroxy;
X1 is a straight-chain alkyl having 5 to 19 carbon atoms or a straight-chain alkoxy having 4 to 18 carbon atoms, wherein the straight-chain alkyl having 5 to 19 carbon atoms and the straight-chain alkoxy having 4 to 18 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino, oxo and phenyl;
Y4 is hydroxy or an alkoxy;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
and R3 is hydrogen, an alkyl or an acyl,
an optically active isomer thereof and a salt thereof.
(15) The benzene compound of (14), having the formula 
wherein W2 is a straight- or branched chain alkyl having 1 to 4 carbon atoms; a straight- or branched chain alkenyl having 2 or 3 carbon atoms; a straight- or branched chain alkynyl having 2 or 3 carbon atoms; or a straight- or branched chain C1-C3 alkyl substituted by 1 to 3 substituents selected from the group consisting of a halogen, a cycloalkyl and a phenyl which may be substituted by hydroxy;
X2 is a straight-chain alkyl having 7 to 12 carbon atoms or a straight-chain alkoxy having 6 to 11 carbon atoms, wherein the straight-chain alkyl having 7 to 12 carbon atoms and the straight-chain alkoxy having 6 to 11 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino and oxo;
Y4 is hydroxy or an alkoxy;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
and R3 is hydrogen, an alkyl or an acyl,
an optically active isomer thereof and a salt thereof.
(16) The benzene compound of (15), having the formula 
wherein W3 is a straight- or branched chain alkyl having 1 to 3 carbon atoms; a straight- or branched chain alkenyl having 2 or 3 carbon atoms; a straight- or branched chain alkynyl having 2 or 3 carbon atoms; or a straight- or branched chain C1-C3 alkyl substituted by 1 to 3 halogens;
X2 is a straight-chain alkyl having 7 to 12 carbon atoms or a straight-chain alkoxy having 6 to 11 carbon atoms, wherein the straight-chain alkyl having 7 to 12 carbon atoms and the straight-chain alkoxy having 6 to 11 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino and oxo;
Y4 is hydroxy or an alkoxy;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
and R3 is hydrogen, an alkyl or an acyl,
an optically active isomer thereof and a salt thereof.
(17) The benzene compound of (14), having the formula 
wherein W2 is a straight- or branched chain alkyl having 1 to 4 carbon atoms; a straight- or branched chain alkenyl having 2 or 3 carbon atoms; a straight- or branched chain alkynyl having 2 or 3 carbon atoms; or a straight- or branched chain C1-C3 alkyl substituted by 1 to 3 substituents selected from the group consisting of a halogen, a cycloalkyl and a phenyl which may be substituted by hydroxy;
X2 is a straight-chain alkyl having 7 to 12 carbon atoms or a straight-chain alkoxy having 6 to 11 carbon atoms, wherein the straight-chain alkyl having 7 to 12 carbon atoms and the straight-chain alkoxy having 6 to 11 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino and oxo;
Y4 is hydroxy or an alkoxy; and
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms,
an optically active isomer thereof and a salt thereof.
(18) The benzene compound of (16), having the formula 
wherein W3 is a straight- or branched chain alkyl having 1 to 3 carbon atoms; a straight- or branched chain alkenyl having 2 or 3 carbon atoms; a straight- or branched chain alkynyl having 2 or 3 carbon atoms; or a straight- or branched chain C1-C3 alkyl substituted by 1 to 3 halogens;
X2 is a straight-chain alkyl having 7 to 12 carbon atoms or a straight-chain alkoxy having 6 to 11 carbon atoms, wherein the straight-chain alkyl having 7 to 12 carbon atoms and the straight-chain alkoxy having 6 to 11 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino and oxo;
Y4 is hydroxy or an alkoxy; and
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms,
an optically active isomer thereof and a salt thereof.
(19) The benzene compound of (18), which is selected from the group consisting of
2-amino-4-(4-heptyloxy-3-methoxyphenyl)-2-methylbutanol,
2-amino-4-(4-heptyloxy-3-hydroxyphenyl)-2-methylbutanol,
2-amino-2-ethyl-4-(4-heptyloxy-3-hydroxyphenyl)butanol and
2-amino-2-[2-(4-heptyloxy-3-hydroxyphenyl)ethyl]pentanol,
an optically active isomer thereof and a salt thereof.
(20) The benzene compound of (18), which is
2-amino-4-(4-heptyloxy-3-methoxyphenyl)-2-methylbutanol,
an optically active isomer thereof and a salt thereof.
(21) The benzene compound of (1), having the formula 
wherein X1 is a straight-chain alkyl having 5 to 19 carbon atoms or a straight-chain alkoxy having 4 to 18 carbon atoms, wherein the straight-chain alkyl having 5 to 19 carbon atoms and the straight-chain alkoxy having 4 to 18 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino, oxo and phenyl;
Y1 is hydrogen, an alkyl, hydroxy or an alkoxy;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
m is 1, 2 or 3; n is 2 or 3;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
R3 is hydrogen, an alkyl or an acyl; and
R4 is hydrogen, an alkyl or an acyl,
an optically active isomer thereof and a salt thereof.
(22) The benzene compound of (21), having the formula 
wherein X1 is a straight-chain alkyl having 5 to 19 carbon atoms or a straight-chain alkoxy having 4 to 18 carbon atoms, wherein the straight-chain alkyl having 5 to 19 carbon atoms and the straight-chain alkoxy having 4 to 18 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino, oxo and phenyl;
Y1 is hydrogen, an alkyl, hydroxy or an alkoxy;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
m is 1, 2 or 3; n is 2 or 3;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
R3 is hydrogen, an alkyl or an acyl; and
R4 is hydrogen, an alkyl or an acyl,
an optically active isomer thereof and a salt thereof.
(23) The benzene compound of (22), having the formula 
wherein X1 is a straight-chain alkyl having 5 to 19 carbon atoms or a straight-chain alkoxy having 4 to 18 carbon atoms, wherein the straight-chain alkyl having 5 to 19 carbon atoms and the straight-chain alkoxy having 4 to 18 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino, oxo and phenyl;
Y2 is hydrogen, hydroxy or an alkoxy;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
m is 1, 2 or 3; n is 2 or 3;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
R3 is hydrogen, an alkyl or an acyl; and
R4 is hydrogen, an alkyl or an acyl,
an optically active isomer thereof and a salt thereof.
(24) The benzene compound of (23), having the formula 
wherein X1 is a straight-chain alkyl having 5 to 19 carbon atoms or a straight-chain alkoxy having 4 to 18 carbon atoms, wherein the straight-chain alkyl having 5 to 19 carbon atoms and the straight-chain alkoxy having 4 to 18 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino, oxo and phenyl;
Y3 is hydrogen or an alkoxy;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
m is 1, 2 or 3; n is 2 or 3;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
R3 is hydrogen, an alkyl or an acyl; and
R4 is hydrogen, an alkyl or an acyl,
an optically active isomer thereof and a salt thereof.
(25) The benzene compound of (22), having the formula 
wherein X1 is a straight-chain alkyl having 5 to 19 carbon atoms or a straight-chain alkoxy having 4 to 18 carbon atoms, wherein the straight-chain alkyl having 5 to 19 carbon atoms and the straight-chain alkoxy having 4 to 18 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino, oxo and phenyl;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
m is 1, 2 or 3; n is 2 or 3;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
R3 is hydrogen, an alkyl or an acyl; and
R4 is hydrogen, an alkyl or an acyl,
an optically active isomer thereof and a salt thereof.
(26) The benzene compound of (25), having the formula 
wherein X2 is a straight-chain alkyl having 7 to 12 carbon atoms or a straight-chain alkoxy having 6 to 11 carbon atoms, wherein the straight-chain alkyl having 7 to 12 carbon atoms and the straight-chain alkoxy having 6 to 11 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino and oxo;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
m is 1, 2 or 3; n is 2 or 3;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
R3 is hydrogen, an alkyl or an acyl; and
R4 is hydrogen, an alkyl or an acyl,
an optically active isomer thereof and a salt thereof.
(27) The benzene compound of (26), having the formula 
wherein X2 is a straight-chain alkyl having 7 to 12 carbon atoms or a straight-chain alkoxy having 6 to 11 carbon atoms, wherein the straight-chain alkyl having 7 to 12 carbon atoms and the straight-chain alkoxy having 6 to 11 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino and oxo;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
m is 1, 2 or 3; and n is 2 or 3,
an optically active isomer thereof and a salt thereof.
(28) The benzene compound of (27), which is selected from the group consisting of
2-amino-2-[3-(4-heptylphenyl)propyl]butane-1,4-diol,
2-amino-2-[3-(4-nonylphenyl)propyl]butane-1,4-diol,
2-amino-2-[3-(4-undecylphenyl)propyl]butane-1,4-diol,
2-amino-2-[2-(4-octylphenyl)ethyl]butane-1,4-diol,
2-amino-2-[2-(4-decylphenyl)ethyl]butane-1,4-diol,
2-amino-2-[2-(4-dodecylphenyl)ethyl]butane-1,4-diol,
2-amino-2-[2-(4-heptyloxyphenyl)ethyl]butane-1,4-diol,
2-amino-2-[2-(4-octylphenyl)ethyl]pentane-1,5-diol,
3-amino-3-[2-(4-octylphenyl)ethyl]pentane-1,5-diol and
3-amino-3-[2-(4-octylphenyl)ethyl]hexane-1,6-diol,
an optically active isomer thereof and a salt thereof.
(29) The benzene compound of (27), which is selected from the group consisting of
2-amino-2-[3-(4-heptylphenyl)propyl]butane-1,4-diol,
2-amino-2-[3-(4-nonylphenyl)propyl]butane-1,4-diol,
2-amino-2-[3-(4-undecylphenyl)propyl]butane-1,4-diol,
2-amino-2-[2-(4-octylphenyl)ethyl]butane-1,4-diol,
2-amino-2-[2-(4-decylphenyl)ethyl]butane-1,4-diol,
2-amino-2-[2-(4-dodecylphenyl)ethyl]butane-1,4-diol,
2-amino-2-[2-(4-heptyloxyphenyl)ethyl]butane-1,4-diol,
2-amino-2-[2-(4-octylphenyl)ethyl]pentane-1,5-diol and
3-amino-3-[2-(4-octylphenyl)ethyl]hexane-1,6-diol,
an optically active isomer thereof and a salt thereof.
(30) The benzene compound of (27), which is
2-amino-2-[3-(4-nonylphenyl)propyl]butane-1,4-diol,
an optically active isomer thereof and a salt thereof.
(31) The benzene compound of (1), having the formula 
wherein X1 is a straight-chain alkyl having 5 to 19 carbon atoms or a straight-chain alkoxy having 4 to 18 carbon atoms, wherein the straight-chain alkyl having 5 to 19 carbon atoms and the straight-chain alkoxy having 4 to 18 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino, oxo and phenyl;
Y1 is hydrogen, an alkyl, hydroxy or an alkoxy;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
and R3 is hydrogen, an alkyl or an acyl,
an optically active isomer thereof and a salt thereof.
(32) The benzene compound of (31), having the formula 
wherein X2 is a straight-chain alkyl having 7 to 12 carbon atoms or a straight-chain alkoxy having 6 to 11 carbon atoms, wherein the straight-chain alkyl having 7 to 12 carbon atoms and the straight-chain alkoxy having 6 to 11 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino and oxo;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
and R3 is hydrogen, an alkyl or an acyl,
an optically-active isomer thereof and a salt thereof.
(33) The benzene compound of (32), having the formula 
wherein X2 is a straight-chain alkyl having 7 to 12 carbon atoms or a straight-chain alkoxy having 6 to 11 carbon atoms, wherein the straight-chain alkyl having 7 to 12 carbon atoms and the straight-chain alkoxy having 6 to 11 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino and oxo; and
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms,
an optically active isomer thereof and a salt thereof.
(34) The benzene compound of (33), which is selected from the group consisting of
2-amino-4-(4-octylphenyl)butanol,
2-amino-4-(4-heptyloxyphenyl)butanol and
2-amino-5-(4-hexyloxyphenyl)pentanol,
an optically active isomer thereof and a salt thereof.
(35) The benzene compound of (1), having the formula 
wherein X1 is a straight-chain alkyl having 5 to 19 carbon atoms or a straight-chain alkoxy having 4 to 18 carbon atoms, wherein the straight-chain alkyl having 5 to 19 carbon atoms and the straight-chain alkoxy having 4 to 18 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino, oxo and phenyl;
Y1 is hydrogen, an alkyl, hydroxy or an alkoxy;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
R3 is hydrogen, an alkyl or an acyl; and
R5 is hydrogen or hydroxy,
an optically active isomer thereof and a salt thereof.
(36) The benzene compound of (35), having the formula 
wherein X2 is a straight-chain alkyl having 7 to 12 carbon atoms or a straight-chain alkoxy having 6 to 11 carbon atoms, wherein the straight-chain alkyl having 7 to 12 carbon atoms and the straight-chain alkoxy having 6 to 11 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino and oxo;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms;
R1 and R2 are the same or different and each is hydrogen, an alkyl or an acyl;
R3 is hydrogen, an alkyl or an acyl; and
R1 is hydrogen or hydroxy,
an optically active isomer thereof and a salt thereof.
(37) The benzene compound of (36), having the formula 
wherein X2 is a straight-chain alkyl having 7 to 12 carbon atoms or a straight-chain alkoxy having 6 to 11 carbon atoms, wherein the straight-chain alkyl having 7 to 12 carbon atoms and the straight-chain alkoxy having 6 to 11 carbon atoms may have 1 to 3 substituents selected from the group consisting of hydroxy, an acyloxy, amino, an acylamino and oxo;
Z1 is a straight-chain alkylene having 2 to 4 carbon atoms; and
R5 is hydrogen or hydroxy,
an optically active isomer thereof and a salt thereof.
(38) The benzene compound of (6), which is 2-amino-2-ethyl-4-(4-(4-phenylbutyloxy)phenyl)butanol, an optically active isomer thereof, a salt thereof or a hydrate thereof.
(39) The benzene compound of (38), which is (xe2x88x92)-2-amino-2-ethyl-4-(4-(4-phenylbutyloxy)phenyl)butanol hydrochloride.
(40) A pharmaceutical composition comprising any one of the compounds of (1) to (39).
(41) A method for immunosuppression of an immune system of a mammal, which comprises administering to a mammal a therapeutically effective amount of a benzene compound of any one of (1) to (39).
(42) The method according to (41), wherein the immunosuppression is suppression of rejection in an organ or bone marrow transplantation.
(43) The method according to (42), wherein the suppression of rejection in an organ or bone marrow transplantation is prevention or treatment of graft-versus-host diseases.
(44) The method according to (41), wherein the immunosuppression is the prevention or treatment of an autoimmune disease.
(45) The method according to (44), wherein the autoimmune disease is rheumatoid arthritis.
(46) The method according to (44), wherein the autoimmune disease is psoriasis or atopic dermatitis.
(47) The method according to (44), wherein the autoimmune disease is bronchial asthma or pollinosis.
(48) The method according to (44), wherein the autoimmune disease is Behget""s disease or uveitis.
(49) The method according to (44), wherein the autoimmune disease is systemic lupus erythematosus.
(50) The method according to (44), wherein the autoimmune disease is multiple sclerosis.
In present invention, compounds of the general formula 
wherein Ra is hydrogen, an alkyl (e.g. methyl, ethyl, propyl, butyl), Rx is carboxy, alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl), aldehyde, vinyl, m1 is 2 or 3, and R1, R2, R3, X, Y, Z, W, m and n are those mentioned above, are useful as synthetic intermediates.
The groups represented by the respective symbols in the present specification are explained in the following.
The straight- or branched chain alkyl having 1 to 6 carbon atoms at W or W1 is exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl. Preferred is a straight- or branched chain alkyl having 1 to 4 carbon atoms, particularly preferred is a straight- or branched chain alkyl having 1 to 3 carbon atoms.
The straight- or branched chain alkyl having 1 to 4 carbon atoms at W2 is exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.
The straight- or branched chain alkyl having 1 to 3 carbon atoms at W3 is exemplified by methyl, ethyl, propyl and isopropyl.
The straight- or branched chain alkenyl having 2 to 6 carbon atoms at W is exemplified by vinyl, allyl, 1-propenyl, 2-butenyl, 3-butenyl, 4-pentenyl and 5-hexenyl. Preferred is a straight- or branched chain alkenyl having 2 or 3 carbon atoms.
The straight- or branched chain alkenyl having 2 or 3 carbon atoms at W2 or W3 is exemplified by vinyl, allyl and 1-propenyl.
The straight- or branched chain alkynyl having 2 to 6 carbon atoms at W is exemplified by propargyl, 2-butynyl, 3-butynyl, 4-pentynyl and 5-hexynyl. Preferred is a straight- or branched chain alkynyl having 2 or 3 carbon atoms.
The straight- or branched chain alkynyl having 2 or 3 carbon atoms at W2 or W3 is exemplified by propargyl.
The phenyl which may be substituted by hydroxy at W is exemplified by phenyl, 4-hydroxyphenyl, 3-hydroxyphenyl and 2-hydroxyphenyl.
The straight- or branched chain C1-C6 alkyl substituted by 1 to 3 substituents selected from the group consisting of a halogen (fluorine, chlorine, bromine, iodine), a cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) and a phenyl which may be substituted by hydroxy at W or W1 is exemplified by fluoromethyl, 2-fluoroethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl, 2, 2, 2-trifluoroethyl, 3-fluoropropyl, 3,3,3-trifluoropropyl, 4-fluorobutyl, 5-fluoropentyl, 6-fluorohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 4-hydroxybenzyl, 3,4-dihydroxybenzyl and 3,4,5-trihydroxybenzyl. Preferred is a straight- or branched chain C1-C3 alkyl substituted by 1 to 3 substituents selected from the group consisting of a halogen, a cycloalkyl and a phenyl which may be substituted by hydroxy, particularly preferred is a straight- or branched chain C1-C3 alkyl which is substituted by 1 to 3 halogens.
The straight- or branched chain C1-C3 alkyl substituted by 1 to 3 substituents selected from the group consisting of a halogen, a cycloalkyl and a phenyl which may be substituted by hydroxy at W2 is exemplified by fluoromethyl, 2-fluoroethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3,3-trifluoropropyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 4-hydroxybenzyl, 3,4-dihydroxybenzyl and 3,4,5-trihydroxybenzyl.
The straight- or branched chain C1-C3 alkyl substituted by 1 to 3 halogens at W3 is exemplified by fluoromethyl, 2-fluoroethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3,3-trifluoropropyl.
The straight-chain alkyl having carbon atoms in the number of p at X is a straight-chain alkyl having 1 to 20 carbon atoms and is exemplified by methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and icosyl. Preferred is a straight-chain alkyl having 5 to 19 carbon atoms, particularly preferred is a straight-chain alkyl having 7 to 12 carbon atoms.
The straight-chain alkyl having 5 to 19 carbon atoms at X1 is exemplified by pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl and nonadecyl.
The straight-chain alkyl having 7 to 12 carbon atoms at X2 is exemplified by heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
The straight-chain alkoxy having carbon atoms in the number of (pxe2x88x921) at X is a straight-chain alkoxy having 1 to 19 carbon atoms and is exemplified by methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy and icosyloxy. Preferred is a straight-chain alkoxy having 4 to 18 carbon atoms, particularly preferred is a straight-chain alkoxy having 6 to 11 carbon atoms.
The straight-chain alkoxy having 4 to 18 carbon atoms at X1 is exemplified by butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy and octadecyloxy.
The straight-chain alkoxy having 6 to 11 carbon atoms at X2 is exemplified by hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and undecyloxy.
The alkyl as a substituent at X is a straight- or branched chain alkyl having 1 to 6 carbon atoms and is exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl. The said alkyl may be substituted by a phenyl which may have 1 to 3 substituents selected from the group consisting of an alkyl, hydroxy, an acyl, an acyloxy, amino, an alkylamino, a haloalkyl and a halogen.
The alkoxy as a substituent at X is a straight- or branched chain alkoxy having 1 to 6 carbon atoms and is exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, tert-pentyloxy and hexyloxy.
The acyloxy as a substituent at X, X1 or X2 is that where the acyl moiety is a straight- or branched chain alkanoyl having 2 to 20 carbon atoms and includes, for example, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy, decanoyloxy, undecanoyloxy, dodecanoyloxy, tridecanoyloxy, tetradecanoyloxy, pentadecanoyloxy, hexadecanoyloxy, heptadecanoyloxy, octadecanoyloxy, nonadecanoyloxy and icosanoyloxy.
The alkylamino as a substituent at X is that where the alkyl moiety is a straight- or branched chain alkyl having 1 to 6 carbon atoms and includes, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, tert-pentylamino and hexylamino.
The acylamino as a substituent at X, X1 or X2 is that where the acyl moiety is a straight- or branched chain alkanoyl, alkoxycarbonyl or aralkoxycarbonyl having 1 to 20 carbon atoms and includes, for example, formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, pentanoylamino, pivaloylamino, hexanoylamino, heptanoylamino, octanoylamino, nonanoylamino, decanoylamino, undecanoylamino, dodecanoylamino, tridecanoylamino, tetradecanoylamino, pentadecanoylamino, hexadecanoylamino, heptadecanoylamino, octadecanoylamino, nonadecanoylamino, icosadecanoylamino, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino and benzyloxycarbonylamino.
The haloalkyl as a substituent at X is that where the alkyl moiety is a straight- or branched chain alkyl having 1 to 6 carbon atoms and includes, for example, fluoromethyl, trifluoromethyl, chloromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 3-chloropropyl, 3-fluoropropyl, 4-chlorobutyl, 4-fluorobutyl, 5-chloropentyl, 6-chlorohexyl and 6-fluorohexyl.
The halogen as a substituent at X is exemplified by fluorine, chlorine, bromine, iodine.
The acyl as a substituent of a phenyl which may have a substituent at X is an alkanoyl or aroyl which may have a substituent, where the alkanoyl is a straight- or branched chain alkanoyl having 1 to 20 carbon atoms and includes, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tertadecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl, and which may have phenyl as a substituent. Examples thereof include phenylacetyl and phenylpropionyl. The aroyl includes benzoyl.
The alkyl, alkoxy, acyloxy, alkylamino, acylamino, haloalkyl and halogen as a substituent of a phenyl which may have a substituent at X are respectively the same as the aforementioned alkyl, alkoxy, acyloxy, alkylamino, acylamino, haloalkyl and halogen as a substituent at X.
The acyl, acyloxy, alkylamino, acylamino, haloalkyl and halogen at Y, the alkyl at Y or Y1 or the alkoxy at Y1, Y2, Y3 or Y4 are respectively the same as the aforementioned acyl, acyloxy, alkylamino, acylamino, haloalkyl, halogen, alkyl and alkoxy as a substituent of a phenyl which may have a substituent at X.
The straight-chain alkylene having carbon atoms in the number of q at Z is a straight-chain alkylene having 1 to 20 carbon atoms and is exemplified by methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, undecamethylene, dodecamethylene, tridecamethylene, tertadecamethylene, pentadecamethylene, hexadecamethylene, heptadecamethylene, octadecamethylene, nonadecamethylene and icosamethylene. Preferred is a straight-chain alkylene having 2 to 4 carbon atoms.
The straight-chain alkylene having 2 to 4 carbon atoms at Z1 is exemplified by ethylene, trimethylene and tetramethylene.
The alkyl at R1 and R2 is the same as the aforementioned alkyl as a substituent at X.
The acyl at R1 and R2 is an alkanoyl, aroyl, alkoxycarbonyl or aralkyloxycarbonyl which may have a substituent, where the alkanoyl is a straight- or branched chain alkanoyl having 1 to 20 carbon atoms and includes, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl, and which may have phenyl as a substituent. Examples thereof include phenylacetyl and phenylpropionyl. The aroyl includes benzoyl. The alkoxycarbonyl is that the alkoxy moiety is a straight- or branched chain alkoxy having 1 to 20 carbon atoms and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, tridecyloxycarbonyl, tetradecyloxycarbonyl, pentadecyloxycarbonyl, hexadecyloxycarbonyl, heptadecyloxycarbonyl, octadecyloxycarbonyl, nonadecyloxycarbonyl and icosyloxycarbonyl. The aralkyloxycarbonyl includes benzyloxycarbonyl.
The alkyl at R3 is the same as the aforementioned alkyl as a substituent at X.
The acyl at R3 is the same as the aforementioned acyl at R1 and R2.
The alkyl at R4 is the same as the aforementioned alkyl as a substituent at X.
The acyl at R4 is the same as the aforementioned acyl at R1 and R2.
Examples of the salts of the compound (I) include salts with inorganic acids, such as hydrochloride, hydrobromide, sulfate and phosphate, salts with organic acid, such as acetate, fumarate, maleate, benzoate, citrate, succinate, malate, methanesulfonate, benzenesulfonate and tartrate. When the salts of the compound (I) are used as pharmaceuticals, preferred are these pharmaceutically acceptable salts. The compounds of the present invention also encompass hydrate and solvates.
When the compounds of the present invention have one or more asymmetric centers in the molecules, various optical isomers are obtained. The present invention also encompasses optical isomers, racemates, diastereomers and the mixture thereof. Moreover, when the compounds of the present invention include geometric isomers, the present invention encompasses cis-compounds, trans-compounds and the mixture thereof. The preferable compounds of the present invention are shown in the following tables. In the table, Me means methyl, Et means ethyl, n-Pr means n-propyl, i-Pr means isopropyl, c-Pr means cyclopropyl, n-Bu means n-butyl, Ac means acetyl, Ph means phenyl, C6H4 means phenylene and Boc means tert-butoxycarbonyl.
The compound of the present invention can be produced according to the following methods.
[Method A]
A compound of the formula (II) [hereinafter referred to as Compound (II)]
wherein Z, X and Y are as defined above. Lv is a leaving group widely employed in the field of organic synthetic chemistry, such as fluorine, chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy, or when X or Y has a functional group (e.g. amino, hydroxy, oxo), the functional group may be protected if necessary; is condensed, in the presence of a base, with a compound of the formula (III) [hereinafter referred to as Compound (III)]
wherein Rc is lower alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl; to give a compound of the formula (IV) [hereinafter referred to as Compound (IV)]
wherein X, Y, Z and Rc are as defined above; which is subjected to condensation with a compound of the formula (V) [hereinafter referred to as Compound (V)]
P1O(CH2)nxe2x80x94Lvxe2x80x83xe2x80x83(V)
wherein P1 is a hydroxy-protecting group widely employed in the field of organic synthetic chemistry, such as acetyl benzoyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, methoxymethyl, methoxyethoxymethyl or tetrahydropyranyl, and n and Lv are as defined above; in the presence of a base, to give a compound of the formula (VI) [hereinafter referred to as Compound (VI)]
wherein X, Y, Z, Rc, n and P1 are as difined above. The ester compound obtained is then subjected to hydrolysis and the Curtius rearrangement reaction, to give a compound of the formula (VII) [hereinafter referred to as Compound (VII)]
wherein Rd is alkyl group or aralkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, benzyl, and X, Y, Z, Rc, n and P1 are as defined above; which is subjected to reduction of ester and protection/deprotection, if necessary, to give compound(s) of the formula (VIII-a) and/or (VIII-b) [hereinafter referred to as Compound (VIII-a) and/or (VIII-b)]
wherein X, Y, Z, R1, R3, R4 and n are as defined above; followed by treatment with an alkali and protection/deprotection, if necessary, to give a compound of the formula (I-1) [hereinafter referred to as Compound (I-1)]
wherein X, Y, Z, R1, R2, R3, R4 and n are as defined above.
Examples of the base to be used in the condensation of Compound (II) and Compound (III) include sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide, lithium hexamethyl-disilazane, diisopropylethylamine and 1,8-diazabicyclo[4.3.0]undec-5-ene.
Examples of the organic solvent to be used in the condensation include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile.
The condensation generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 150xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The condensation is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the condensation is carried out under the above-mentioned conditions or after removing the protecting group on demand, the Compound (IV) can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
The condensation of the second process in the present method is carried out under the above-mentioned conditions.
Examples of the base to be used in the hydrolysis of Compound (VI) include sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide.
Examples of the organic solvent to be used in hydrolysis include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, ethylene glycol dimethyl ether, dimethylformamide and dimethyl sulfoxide, and a mixed solvent with water thereof can be used if necessary.
The hydrolysis generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The hydrolysis is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the hydrolysis is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the base to be used in the Curtius rearrangement reaction include hxc3x6nig base such as triethylamine or diusopropylethylamine, provided that carboxylic acid in the reaction substrate form a salt, none of the aforementioned base need to be used.
Examples of the activating agent to be used in the Curtius rearrangement reaction include methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, isobutyl chloroformate and phenyl chloroformate.
Examples of the azidation agent to be used in the Curtius rearrangement reaction include sodium azide and diphenylphosphoric azide, provided that diphenylphosphoric azide is used, both the aforementioned base and activating agent are not necessary to employ.
The solvent to be used in the Curtius rearrangement reaction is preferably non-protonic solvent at the first half of the reaction and is exemplified by tetrahydrofuran, acetone, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, dioxane, metylene chloride, chloroform, dichloroethane and acetonitrile, and is exemplified, at the latter half of the reaction, by methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane, acetonitrile and benzyl alcohol.
The Curtius rearrangement reaction generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 150xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The Curtius rearrangement reaction is generally carried out for 30 minutes to 10 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the Curtius rearrangement reaction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the reducing agent in the reduction of ester include metallic reducing reagent such as diborane, sodium borohydride, lithium borohydride or lithium aluminum hydride.
Examples of the organic solvent to be used in the reduction include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether.
The reduction generally proceeds at a temperature of from xe2x88x92100xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The reduction is generally carried out for 30 minutes to 10 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the reduction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the alkali to be used in the alkaline treatment of Compound (VIII-a) and/or (VIII-b) include sodium hydroxide and potassium hydroxide.
Examples of the solvent to be used in the present reaction include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, water and a mixture thereof.
The reaction generally proceeds at a temperature of from 50xc2x0 C. to the refluxing temperature of the solvent to be used and a lower or higher temperature than said temperature range may be selected on demand.
The reaction is generally carried out for 30 minutes to 12 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the reaction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
In the present method, Compound (I-1) also can be produced directly without through Compound (VII) to Compound (VIII-a) and/or (III-b)
[Method B]
The Compound (VI) in Method A also can be produced according to the following method. Namely, Compound (III) and Compound (V) are condensed in the presence of a base to give a compound of the formula (IX) [hereinafter referred to as Compound (IX)]
wherein Rc, P1 and n are as defined above; which is subjected to condensation, in the presence of a base, with Compound (II) to give Compound (VI). Each condensation reaction in the present method is also carried out under the same conditions of the condensation in Method A.
[Method C]
Compound (VI) to be produced according to Method A is deprotected selectively and is then treated with an acid or a base to give a compound of the formula (X) [hereinafter referred to as Compound (X)]
wherein X, Y, Z, Rc and n are as defined above; which is subjected to hydrolysis and then Curtius rearrangement reaction, and is further protected/deprotected, if necessary, to give a compound of the formula (XI) [hereinafter referred to as Compound (XI)]
wherein X, Y, Z, R1, R2 and n are as defined above; which is subjected to reduction and is protected/deprotected, if necessary, to give Compound (I-1).
Examples of the base to be used in the hydrolysis include sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide.
Examples of the solvent to be used in the hydrolysis include water, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, ethylene glycol dimethyl ether, dimethylformamide and dimethyl sulfoxide.
The hydrolysis generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The hydrolysis is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the reaction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the base to be used in the Curtius rearrangement reaction include hxc3x6nig base such as triethylamine or diisopropylethylamine, provided that carboxylic acid in the reaction substrate form a salt, none of the aforementioned base need to be used.
Examples of the activating agent to be used in the Curtius rearrangement reaction include methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, isobutyl chloroformate and phenyl chloroformate.
Examples of the azidation agent to be used in the Curtius rearrangement reaction include sodium azide and diphenylphosphoric azide, provided that diphenylphosphoric azide is used, both the aforementioned base and activating agent are not necessary to employ.
The solvent to be used in the Curtius rearrangement reaction is preferably non-protonic solvent at the first half of the reaction and is exemplified by tetrahydrofuran, acetone, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, dioxane, metylene chloride, chloroform, dichloroethane and acetonitrile, and is exemplified, at the latter half of the reaction, by methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane, acetonitrile and benzyl alcohol.
The Curtius rearrangement reaction generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 150xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The Curtius rearrangement reaction is generally carried out for 30 minutes to 10 hours and the longer or shorter reaction period than a indicated period may be selected on demand.
After the Curtius rearrangement reaction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the reducing agent in the reduction include metallic reducing reagent such as diborane, sodium borohydride, lithium borohydride or lithium aluminum hydride.
Examples of the organic solvent to be used in the reduction include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether.
The reduction generally proceeds at a temperature of from xe2x88x92100xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The reduction is generally carried out for 30 minutes to 10 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the reduction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
[Method D]
Compound (XI) in Method C also can be produced according to the following method.
Namely, a compound of the formula (XII-a) [hereinafter referred to as Compound (XII-a)]
wherein n is as defined above; and benzophenoneimine are condensed to give a compound of the formula (XII-b) [hereinafter referred to as Compound (XII-b)]
wherein Ph is phenyl and n is as defined above; and Compound (XII-b) and Compound (II) are condensed, in the presence of a base, to give a compound of the formula (XIII) [hereinafter referred to as Compound (XIII)]
wherein X, Y, Z, Ph and n are as defined above; which is subjected to hydrolysis and protection/deprotection, if necessary, to give Compound (XI).
Examples of the organic solvent to be used in the condensation with benzophenoneimine include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile.
The condensation generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 50xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The condensation is generally carried out for 30 minutes to 24 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the condensation is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the base to be used in the condensation with Compound (II) include sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide, lithium hexamethyldisilazane, diisopropylethylamine and 1,8-diazabicyclo[4.3.0]undec-5-ene.
Examples of the organic solvent to be used in the condensation include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile.
The condensation generally proceeds at a temperature of from xe2x88x92100xc2x0 C. to 150xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The condensation is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the condensation is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the reagent to be used in the hydrolysis include hydrochloric acid, sulfuric acid, acetic acid and trifluoroacetic acid.
Examples of the solvent to be used in the hydrolysis include water, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, ethylene glycol dimethyl ether, dimethylformamide and dimethyl sulfoxide.
The hydrolysis generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The hydrolysis is generally carried out for 30 minutes to 5 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the hydrolysis is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
[Method E]
A compound of the formula (XIV) [hereinafter referred as to Compound (XIV)]
wherein Wa is a straight- or branched chain alkyl having 1 to 6 carbon atoms; a straight- or branched chain alkenyl having 2 to 6 carbon atoms; a straight- or branched chain alkynyl having 2 to 6 carbon atoms; a phenyl which may be substituted by hydroxy; or a straight- or branched chain C1-C6 alkyl substituted by 1 to 3 substituents selected from the group consisting of a halogen, a cycloalkyl and a phenyl which may be substituted by hydroxy, Rc is as defined above, when Wa has hydroxy, the hydroxy may be protected if necessary; is condensed, in the presence of a base, with Compound (II) to give a compound of the formula (XV) [hereinafter referred as to Compound (XV)]
wherein Wa, X, Y, Z and Rc are as defined above; which is hydrolyzed, followed by Curtius rearrangement reaction to give a compound of the formula (XVI) [hereinafter referred as to Compound (XVI)]
wherein Wa, X, Y, Z, Rc and Rd are as defined above. The ester compound obtained is reduced and subjected to protection/deprotection, if necessary, to give a compound of the formula (XVII) [hereinafter referred as to Compound (XVII)]
wherein Wa, X, Y, Z and R1 are as defined above; followed by treatment with an alkali and protection/deprotection, if necessary, to give a compound of the formula (I-2) [hereinafter referred as to Compound (I-2)]
wherein Wa, X, Y, Z, R1, R2 and R3 are as defined above.
Examples of the base to be used in the condensation with Compound (II) include sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide, lithium hexamethyldisilazane, diisopropylethylamine and 1,8-diazabicyclo[4.3.0]undec-5-ene.
Examples of the organic solvent to be used in the condensation include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile.
The condensation generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 150xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The condensation is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the condensation is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the base to be used in the hydrolysis of Compound (XV) include sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide.
Examples of the organic solvent to be used in hydrolysis include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, ethylene glycol dimethyl ether, dimethylformamide and dimethylsulfoxide, and a mixed solvent with water thereof can be used if necessary.
The hydrolysis generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The hydrolysis is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the hydrolysis is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the base to be used in the Curtius rearrangement reaction include hxc3x6nig base such as triethylamine or diisopropylethylamine, provided that carboxylic acid in the reaction substrate form a salt, none of the aforementioned base need to be used.
Examples of the activating agent to be used in the Curtius rearrangement reaction include methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, isobutyl chloroformate and phenyl chloroformate.
Examples of the azidation agent to be used in the Curtius rearrangement reaction include sodium azide and diphenylphosphoric azide, provided that diphenylphosphoric azide is used, both the aforementioned base and activating agent are not necessary to employ.
Examples of the solvent to be used in the Curtius rearrangement reaction is preferably non-protonic solvent at the first half of the reaction and is exemplified by tetrahydrofuran, acetone, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile, and is exemplified, at the latter half of the reaction, by methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane, acetonitrile and benzyl alcohol.
The Curtius rearrangement reaction generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 150xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The Curtius rearrangement reaction is generally carried out for 30 minutes to 10 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the Curtius rearrangement reaction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the reducing agent to be used in the reduction of Compound (XVI) include metallic reducing reagent such as sodium borohydride, lithium borohydride or aluminum hydride.
Examples of the organic solvent to be used in the reduction include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether. The reduction generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The reduction is generally carried out for 30 minutes to 10 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the reduction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the alkali to be used in the alkaline treatment of Compound (XVII) include sodium hydroxide and potassium hydroxide.
Examples of the organic solvent to be used in the present reaction include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, water and a mixture thereof.
The present reaction generally proceeds at a temperature of from 50xc2x0 C. to the refluxing temperature of the solvent to be used and a lower or higher temperature than said temperature range may be selected on demand.
The present reaction is generally carried out for 30 minutes to 12 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the present reaction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
In the present method, Compound (I-2) also can be produced directly from Compound (XVI) without through Compound (XVII).
[Method F]
Compound (XIV) also can be produced according to the following method.
Namely, a compound of the formula (XVIII) [hereinafter referred to as Compound (XVIII)]
Waxe2x80x94Lvxe2x80x83xe2x80x83(XIII)
wherein Wa and Lv are as defined above; and Compound (III) are condensed in the presence of a base, to give Compound (XIV).
Examples of the base to be used in the condensation of Compound (XVIII) and Compound (III) include sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide, lithium hexamethyldisilazane, diisopropylethylamine and 1,8-diazabicyclo[4.3.0]undec-5-ene.
Examples of the organic solvent to be used in the condensation include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile.
The condensation generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 150xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The condensation is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the condensation is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
[Method G]
Compound (XV) in Method F also can be produced according to the following method.
Namely, Compound (IV) and Compound (XVIII) are condensed in the presence of a base to give Compound (XV).
Examples of the base to be used in the condensation of Compound (IV) and Compound (XVIII) include sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide, lithium hexamethyldisilazane, diisopropylethylamine and 1,8-diazabicyclo[4.3.0]undec-5-ene.
Examples of the organic solvent to be used in the condensation include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile.
The condensation generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 150xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The condensation is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the condensation is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
[Method H]
A compound of the formula (XIX) [hereinafter referred to as Compound (XIX)]
wherein P2 is an amino-protecting group widely employed in the field of organic synthetic chemistry, such as acetyl, benzoyl, benzyl, tert-butoxy-carbonyl or benzyloxycarbonyl, Rc is as defined above; and Compound (II) are condensed in the presence of a base to give a compound of the formula (XX) [hereinafter referred to as Compound (XX)]
wherein X, Y, Z, P2 and Rc are as defined above; which is subjected to hydrolysis and then decarboxylation at the same time, followed by protection/deprotection, if necessary, to give a compound of the formula (XXI) [hereinafter referred to as Compound (XXI)]
wherein Re is hydrogen or an carboxyl-protecting group widely employed in the field of organic synthetic chemistry, such as methyl, ethyl, tert-butyl or benzyl, and X, Y, Z, R1 and R2 are as defined above; the carboxyl compound obtained is reduced and then subjected to protection/deprotection, if necessary, to give a compound of the formula (I-3) [hereinafter referred to as Compound (I-3)]
wherein X, Y, Z, R1, R2 and R3 are as defined above.
Examples of the base to be used in the condensation with Compound (II) include sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide, lithium hexamethyldisilazane, diisopropylethylamine and 1,8-diazabicyclo[4.3.0]undec-5-ene.
Examples of the organic solvent to be used in the condensation include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile.
The condensation generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 150xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The condensation is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the condensation is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the reagent to be used in the hydrolysis and decarboxylation of Compound (XX) include hydrochloric acid, sulfuric acid, acetic acid and trifluoroacetic acid.
Examples of the solvent to be used in hydrolysis and decarboxylation include water, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, ethylene glycol dimethyl ether, dimethylformamide and dimethyl sulfoxide.
The hydrolysis and decarboxylation generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 150xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The hydrolysis and decarboxylation is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the hydrolysis and decarboxylation is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the reducing agent to be used in the reduction of Compound (XXI) include borane, metallic reducing reagent such as sodium borohydride, lithium borohydride and lithium aluminum hydride.
Examples of the organic solvent to be used in the reduction include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether.
The reduction generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The reduction is generally carried out for 30 minutes to 10 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the reduction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
[Method I]
A compound of the formula (XXII) [hereinafter referred to as Compound (XXII)]
wherein Met is a metal widely employed in the field of organic synthetic chemistry, such as lithium, magnesium chloride, magnesium bromide, magnesium iodide, copper, lithium copper and nickel, j is an integer of 1 to 3, X, Y and Z are as defined above, or when X or Y has a functional group (e.g. amino, hydroxy, oxo), the functional group may be protected if necessary; is subjected to addition with a compound of the formula (XXIII) [hereinafter referred to as Compound (XXIII)]
wherein Rf and Rg are a lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl) and Rf and Rg may together form an alkylene (e.g. ethylene, propylene), m1 and n are as defined above; to give a compound of the formula (XXIV) [hereinafter referred to as Compound (XXIV)]
wherein Rf, Rg, X, Y, Z, m1 and n are as defined above; which is subjected to Ritter reaction and then hydrolysis to give a compound of the formula (XXV) [hereinafter referred to as Compound (XXV)]
wherein P4 is an acyl such as formyl, acetyl or benzoyl, and X, Y, Z, m1 and n are as defined above; followed by Baeyer-Villiger reaction and then protection/deprotection, if necessary, to give a compound of the formula (XXVI) [hereinafter referred to as Compound (XXVI)]
wherein X, Y, Z, R1, R2, m1 and n are as defined above; and Compound (XXVI) is reduced and then subjected to protection/deprotection, if necessary, to give a compound of the formula (I-4) [hereinafter referred to as Compound (I-4)]
wherein X, Y, Z, R1, R2, R3, R4, m and n are as defined above.
Examples of the organic solvent to be used in the addition with Compound (XXIII) include tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform and dichloroethane.
The addition generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 100xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The addition is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the addition is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the reagent to be used in the Ritter reaction of Compound (XXIV) include hydrogen cyanide, acetonitrile and benzonitrile.
Examples of the organic solvent to be used in the Ritter reaction include acetic acid, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform and dichloroethane.
Examples of the acid catalyst to be used in the Ritter reaction include a strong acid such as sulfuric acid or trifluoroacetic acid.
The Ritter reaction generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The Ritter reaction is generally carried out for 30 minutes to 24 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the Ritter reaction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the reagent to be used in the hydrolysis include hydrochloric acid, sulfuric acid, acetic acid and trifluoroacetic acid.
Examples of the solvent to be used in the hydrolysis include water, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, acetone, tetrahydrofuran, ethylene glycol dimethyl ether, dimethylformamide and dimethyl sulfoxide.
The hydrolysis generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 100xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The condensation is generally carried out for 30 minutes to 5 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the hydrolysis is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the oxidizing agent to be used in the Baeyer-Villiger reaction of Compound (XXV) include peracetic acid, hydrogen peroxide and metachloroperbenzoic acid.
Examples of the organic solvent to be used in the Baeyer-Villiger reaction include tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, carbon tetrachloride and dichloroethane.
The Baeyer-Villiger reaction generally proceeds at a temperature of from 0xc2x0 C. to 100xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The Baeyer-Villiger reaction is generally carried out for 30 minutes to 24 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the Baeyer-Villiger reaction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the reducing agent to be used in the reduction of Compound (XXVI) include borane, metallic reducing reagent such as sodium borohydride, lithium borohydride or lithium aluminum hydride.
Examples of the solvent to be used in the reduction include water, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, tetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether.
The reduction generally proceeds at a temperature of from xe2x88x92100xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The reduction is generally carried out for 30 minutes to 10 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the reduction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
[Method J]
Compound (I-4) also can be produced according to the following method.
Namely, a compound of the formula (XXVII) [hereinafter referred to as Compound (XXVII)]
wherein m1 and n are as defined above; is subjected to addition with Compound (XXII) to give a compound of the formula (XXVIII) [hereinafter referred to as Compound (XXVIII)]
wherein X, Y, Z, m1 and n are as defined above; which is subjected to Ritter reaction to give a compound of the formula (XXIX) [hereinafter referred to as Compound (XXIX)]
wherein X, Y, Z, P4, m1 and n are as defined above; the double bond in the compound obtained is subjected to oxidative cleavage reaction and then reduction and/or protection/deprotection, if necessary, to give Compound (I-4).
Examples of the organic solvent to be used in the addition with Compound (XXII) include tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform and dichloroethane.
The addition generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 100xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The addition is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the addition is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the reagent to be used in the Ritter reaction of Compound (XXVIII) include hydrogen cyanide, acetonitrile and benzonitrile.
Examples of the organic solvent to be used in the Ritter reaction include acetic acid, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform and dichloroethane.
Examples of the acid catalyst to be used in the Ritter reaction include a strong acid such as sulfuric acid or trifluoroacetic acid.
The Ritter reaction generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The Ritter reaction is generally carried out for 30 minutes to 24 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the Ritter reaction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the reagent to be used in the oxidative cleavage reaction of Compound (XXIX) include ozone, potassium permanganate, osumic acid-sodium metaperiodate and osumic acid-lead tetraacetate.
Examples of the solvent to be used in the oxidative cleavage reaction include water, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, acetone, acetic acid, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, ethyl acetate, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and pyridine.
The oxidative cleavage reaction generally proceeds at a temperature of from xe2x88x92100xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The oxidative cleavage reaction is generally carried out for 30 minutes to 24 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the oxidative cleavage reaction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
[Method K]
A compound of the formula (XXX) [hereinafter referred to as Compound (XXX)]
wherein W, X, Y, Z, R1, R3 and m are as defined above, is divided into an optically active isomer thereof and, if necessary, is subjected to protection/deprotection to give a compound of the formula (XXX-a) or (XXX-b) 
wherein W, X, Y, Z, R1, R3 and m are as defined above.
A method dividing into an optically active isomer is inclusive of the following methods: (1) a salt, an ester or an acid amide of Compound (XXX) is formed with an optically active acid such as (+)- or (xe2x88x92)-tartaric acid, (+)- or (xe2x88x92)-mandelic acid, (+)- or (xe2x88x92)-malic acid, (+)- or (xe2x88x92)-dibenzoyltartaric acid, (+)- or (xe2x88x92)-aspartic acid, (S)- or (R)-1-phenylethanesulfonic acid, (+)- or (xe2x88x92)-10-camphorsulfonic acid or (S)- or (R)-xcex1-methoxy-xcex1-trifluoromethylphenylacetic acid, and is subjected to recrystallization or chromatography; (2) Compound (XXX) is directly subjected to high performance liquid chromatography using a chiral carrier [e.g. CROWNPAK CR (trademark, Daicel Chemical Industries); or (3) Compound (XXX) is subjected to N-acylation with 3,5-dinitrobenzoyl chloride etc. and then is subjected to high performance liquid chromatography using a chiral carrier [e.g. CHIRALCEL OD (trademark, Daicel Chemical Industries), CHIRALCEL OG (trademark, Daicel Chemical Industries), CHIRALCEL OF (trademark, Daicel Chemical Industries)].
After the reaction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the object compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
[Method L]
Compound (I-3) also can be produced according to the following method.
Namely, a compound of the formula (XXXI) [hereinafter referred to as Compound (XXXI)] derived from an amino acid: serine or an ester thereof 
wherein Rc and P2 are as defined above; is reacted, in the presence of an acid catalyst, with 2,2-dimethoxypropane to give a compound of the formula [hereinafter referred to as Compound (XXXII)]
wherein Rc and P2 are as defined above. The carboxyl acid or ester of the compound obtained is reduced to give a compound of the formula (XXXIII) [hereinafter referred to as Compound (XXXIII)]
wherein P2 is as defined above; which is condensed, in the presence of a base, with a compound of the formula (XXXIV) [hereinafter referred to as compound (XXXIV)]
wherein Hal is a halogen such as chlorine, bromine or iodine, ZB is a single bond or a straight-chain alkylene having carbon atoms in the number of (qxe2x88x921), X and Y are as defined above; to give a compound of the formula (XXXV) [hereinafter referred to as Compound (XXXV)]
wherein X, Y, ZB and P2 are as defined above; and Compound (XXXV) is reduced to give a compound of the formula (XXXVI) [hereinafter referred to as Compound (XXXVI)]
wherein X, Y, ZB ahd P2 are as defined above; which is subjected to protection/deprotection to give a compound of the formula (I-3).
Compound (XXXI) can be produced according to a method widely employed in the field of organic synthetic chemistry such as reacting serine or an ester thereof with acetyl chloride, benzoyl chloride, di-tert-butyl oxalate or benzyl chloroformate etc.
Examples of the acid catalyst using in the production of Compound (XXXII) include p-toluenesulfonic acid and borone trifluoride ether complex.
Examples of the organic solvent to be used in the present reaction include tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile.
The present reaction generally proceeds at a temperature of from room temperature to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The present reaction is generally carried out for 5 hours to 24 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the reaction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
The reduction of the carboxylic acid or ester can be carried out according to (1) a method using a reducing agent such as diisobutyl aluminum hydride or lithium aluminum hydride, (2) a method using reducing agent such as lithium aluminum hydride, sodium aluminum bis(2-methoxyethoxy) hydride, lithium aluminum trimethoxy hydride or lithium aluminum triethoxy hydride after amidation using ammonia or N, O-dimethylhydroxylamine. When an reduction isomer obtained is an alcohol, the alcohol can be oxidated to give the aldehyde using Swern oxidation or pyridinium chlorochromate (PCC) oxidation.
Examples of the organic solvent to be used in the reduction include hexane, benzene, toluene, methylene chloride, tetrahydrofuran and diethyl ether.
The reduction generally proceeds at a temperature of from xe2x88x9278xc2x0 C. to 100xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The reduction is generally carried out for 5 hours to 24 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the reaction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the base to be used in the condensation with Compound (XXXIV) include sodium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, potassium hydride, lithium diisopropylamide, butyl lithium, lithium hexamethyldisilazane, triethylamine, diisopropylethylamine, pyridine and 1,8-diazabicyclo[4.3.0]undec-5-ene.
Examples of the solvent to be used in the condensation include water, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile.
The condensation generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 150xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The condensation is generally carried out for 30 minutes to 24 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the condensation is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the reducing agent to be used in the reduction of a double bond include a metallic reducing reagent such as lithium borohydride or lithium aluminum hydride, transition metal (palladium-carbon, platinum oxide, Raney nickel, rhodium or ruthenium) for catalytic reduction.
Examples of the organic solvent to be used in the reduction include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, dioxane, acetone, ethyl acetate, acetic acid, benzene, toluene, xylene, dimethylformamide and dimethyl sulfoxide.
The reduction generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The reduction is generally carried out for 30 minutes to 24 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the reduction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Moreover, Compound (XXXVI) is treated with an acid catalyst such as p-toluenesulfonic acid in a solvent such as methanol, or with trifluoroacetic acid, and then removed the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
[Method M]
Using a method shown in from Method A to Method L and from Method P to Method V as mentioned later, a compound of the formula (XXXVII) [hereinafter referred to as Compound (XXXVII)]
wherein ZA is a single bond or a straight-chain alkyl having carbon atoms in the number of r, r is an integer of from 1 to 20, W, R1, R2, R3 and m are as defined above, and when W has a functional group (e.g. hydroxy), the functional group may be protected if necessary; can be produced.
The present method is the method to produce Compound (I) using Compound (XXXVII) as a starting material. Namely, Compound (XXXVII) and a compound of the formula (XXXVIII) [hereinafter referred to as Compound (XXXVIII)]
XACOClxe2x80x83xe2x80x83(XXXVIII)
wherein XA is a straight-chain alkyl having carbon atoms in the number of (pxe2x88x921) (p is as defined above), the said straight-chain alkyl may have 1 to 3 substituents selected from the group consisting of an alkyl, hydroxy, an alkoxy, an acyloxy, amino, an alkylamino, an acylamino, oxo, a haloalkyl, a halogen and a phenyl which may have substituents, and when XA has a functional group (e.g. amino, hydroxy, oxo), the functional group may be protected if necessary; is subjected to Friedel-Crafts reaction in the presence of an acid, and protection/deprotection, if necessary, to give a compound of the formula (I-5) 
wherein W, Z, XA, R1, R2, R3 and m are as defined above.
Examples of the acid to be used in the Friedel-Crafts reaction include aluminum chloride, aluminum bromide, titanium chloride, sulfuric acid, zinc chloride, ferric chloride, hydrogen fluoride and phosphoric acid.
Examples of the organic solvent to be used in the Friedel-Crafts reaction include tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, dichloroethane, acetonitrile, nitromethane and carbon disulfide. The present reaction may be carried out without a solvent if necessary.
The Friedel-Crafts reaction generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 100xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The Friedel-Crafts reaction is generally carried out for 30 minutes to 24 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the Friedel-Crafts reaction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
[Method N]
Compound (I-5) obtained in Method L is subjected to reduction and then protection/deprotection, if necessary, to give a compound of the formula (I-6) [hereinafter referred to as Compound (I-6)]
wherein W, Z, XA, R1, R2, R3 and m are as defined above.
In the reduction, Clemmensen reaction or Wolff-Kishner reaction widely employed in the field of organic synthetic chemistry can be used, but the following reaction is especially useful for the present reaction.
Examples of the reagent to be used in the reduction include triethylsilane.
Examples of the organic solvent to be used in the reduction include trifluoroacetic acid, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, dichloroethane, acetonitrile and nitromethane.
The reduction generally proceeds at a temperature of from 0xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The reduction is generally carried out for 30 minutes to 10 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the reduction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
[Method O]
Using a method shown in from Method A to Method L and from Method P to Method V as mentioned later, a compound of the formula (XXXIX) [hereinafter referred to as Compound (XXXIX)]
wherein W, ZA, R1, R2, R3 and m are as defined above, and when W has a functional group (e.g. hydroxy), the functional group may be protected if necessary; can be produced.
The present method is the method to produce Compound (I) using Compound (XXXIX) as a starting material. Namely, Compound (XXXIX) and a compound of the formula (XL) [hereinafter referred to as Compound (XL)]
XAxe2x80x94Lvxe2x80x83xe2x80x83(XL)
wherein XA and Lv are as defined above, and when XA has a functional group (e.g. amino, hydroxy, oxo), the functional group may be protected if necessary; are subjected to condensation in the presence of a base, and then protection/deprotection, if necessary, to give a compound of the formula (I-7) [hereinafter referred to as Compound (I-7)]
wherein W, Z, XA, R1, R2, R3 and m are as defined above.
Examples of the base to be used in the condensation include sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide, lithium hexamethyldisilazane, diisopropylethylamine, 1,8-diazabicyclo[4.3.0]undec-5-ene.
Examples of the organic solvent to be used in the condensation include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile.
The condensation generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 150xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The condensation is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the condensation is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
[Method P]
The present method is especially useful for the production of a compound of the formula (I) wherein W is an alkyl substituted by a halogen. Namely, Compound (I-1) is subjected to protection/deprotection, if necessary, and then condensation with triethyl orthoacetate [CH3C(OCH2CH3)3] to give a compound of the formula (XLI) [hereinafter referred to as Compound (XLI)]
wherein X, Y, Z and n are as defined above. The free hydroxyl group in the compound obtained is halogenated, and protection/deprotection, if necessary, is subjected to give a compound of the formula (I-8) [hereinafter referred to as Compound (I-8)]
wherein R1, R2, R3, X, Y, Z, n and Hal are as defined above.
Examples of the organic solvent to be used in the condensation of Compound (I-1) and triethyl orthoacetate include tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile.
The condensation generally proceeds at a temperature of from 20xc2x0 C. to 150xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The condensation is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the condensation is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the halogenating reagent to be used in the halogenation include a reagent widely employed in the field of organic synthetic chemistry, for example, hydrogen halide such as hydrochloric acid, hydrobromic acid or hydroiodic acid, phosphorous halide such as phosphorous chloride, phosphorous bromide, phosphorous pentachloride or phosphorous oxychloride, halogen such as chlorine, bromine or iodine, metal halide such as sodium bromide, sodium iodide, or potassium iodide, thionyl chloride, carbon tetrachloride-triphenylphosphine and carbon tetrabromide-triphetiylphosphine. The following reagent is especially useful as the halogenating reagent to be used in the halogenation of Compound (XLI). Namely, examples of the halogenating reagent include N-chlorosuccinimide-triphenylphosphine for the chlorination, N-bromosuccinimide-triphenylphosphine for the bromination, and paratosyl fluoride-tetrabutylammonium fluoride for the fluorination.
Examples of the organic solvent to be used in the halogenation include tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene dioxane, methylene chloride, chloroform, carbon tetrachloride, dichloroethane and acetonitrile. Methylene chloride is preferred in the chlorination and bromination, and tetrahydrofuran is preferred in the fluorination.
The halogenation generally proceeds at a temperature of from 20xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The halogenation is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the halogenation is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization chromatography or a method using an ion exchange resin.
[Method Q]
The present method is especially useful for the production of a compound of the formula (I) wherein W is 1-alkenyl such as vinyl. Namely, by using the manufacturing process disclosed in WO94/08943 or the method reported in Bioorganic and Medicinal Chemistry Letters, Vol.5, No.8, 853-856 (1995) and by performing a selective protection, a compound of the formula(XLII) [hereinafter referred to as Compound (XLII)]
wherein X, Y, Z, P1 and P2 are as defined above; can be produced, Compound (XLII) is oxidized and subjected to protection/deprotection, if necessary, to give a compound of the formula (XLIII) [hereinafter referred to as Compound (XLIII)]
wherein X, Y, Z, P1 and P2 are as defined above; which is condensed, in the presence of a base, with a compound of the formula (XLIV) [hereinafter referred to as Compound (XLIV)]
wherein Ri is hydrogen or a straight- or branched chain alkyl having 1 to 5 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl), Hal is as defined above; and then subjected to protection/deprotection, if necessary, to give a compound of the formula (I-9) [hereinafter referred to as Compound (I-9)]
wherein R1, R2, R3, X, Y, Z and Ri are as defined above.
As a method for oxidizing alcohol to aldehyde, Collins oxidation, Jones oxidation, pyridinium chlorochromate (PCC) oxidation, pyridinium dichromate (PDC) oxidation and Swern oxidation widely employed in the field of organic synthetic chemistry are useful.
Collins oxidation is carried out using chromium (VI) oxide-pyridine complex prepared from chromium (VI) oxide and pyridine in a solvent such as methylene chloride. Collins oxidation generally proceeds at a temperature of from 0xc2x0 C. to 70xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand. Collins oxidation is generally carried out for 10 minutes to 24 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
Jones oxidation is carried out using a solution of chromium (VI) oxide in a dilute sulfuric acid in a solvent such as acetone. Jones oxidation generally proceeds at a temperature of from 0xc2x0 C. to 70xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand. Jones oxidation is generally carried out for 10 minutes to 24 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
The oxidation with pyridinium chlorochromate or pyridinium dichromate is carried out in a solvent such as methylene chloride or benzene. The oxidation generally proceeds at a temperature of from 0xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand. The oxidation is generally carried out for 10 minutes to 24 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
Swern oxidation is carried out using dimethyl sulfoxide-oxalyl chloride in a solvent such as methylene chloride and treating with a base such as triethylamine. Swern oxidation generally proceeds at a temperature of from xe2x88x9278xc2x0 C. to room temperature and a lower or higher temperature than said temperature range may be selected on demand. Swern oxidation is generally carried out for 10 minutes to 24 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the oxidation is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the base to be used in the condensation include sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, n-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium hexamethyldisilazane, diisopropylethylamine and 1,8-diazabicyclo[4.3.0]undec-5-ene.
Examples of the organic solvent to be used in the condensation include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile.
The condensation generally proceeds at a temperature of from xe2x88x9278xc2x0 C. to 100xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The condensation is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the condensation is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Compound (II) can be produced according to the following method.
[Method R]
Compound (II) wherein X is a straight-chain alkyl having carbon atoms in the number of p, which may have 1 to 3 substituents selected from the group consisting of an alkyl, hydroxy, an alkoxy, an acyloxy, amino, an alkylamino, an acylamino, oxo, a haloalkyl, a halogen and a phenyl which may have substituents, the said group is substituted at the p-position of the substituent Lvxe2x80x94Z, Y is hydrogen, and Lv is a halogen, can be produced according to the following method. Namely, a compound of the formula (XLV) [hereinafter referred to as Compound(XLV)]
wherein P1 and Z are as defined above; and a compound of the formula (XLVI) [hereinafter referred to as Compound (XLVI)]
XACOClxe2x80x83xe2x80x83(XLVI)
wherein XA is as defined above, when XA has a functional group (e.g. amino, hydroxy, oxo), the functional group may be protected if necessary; are, in the presence of an acid, subjected to Friedel-Crafts reaction to give a compound of the formula (XLVII) [hereinafter referred to as Compound (XLVII)]
wherein P1, XA and Z are as defined above; which is reduced and subjected to protection/deprotection, if necessary, to give a compound of the formula (XLVIII) [hereinafter referred to as Compound (XLVIII)]
wherein XA and Z are as defined above; which is halogenated and subjected to protection/deprotection, if necessary, to give a compound of the formula (XLIX) [hereinafter referred to as Compound (XLIX)]
wherein Hal, XA and Z are as defined above.
Examples of the acid to be used in the Friedel-Crafts reaction include aluminum chloride, aluminum bromide, titanium chloride, sulfuric acid, zinc chloride, ferric chloride, hydrogen fluoride and phosphoric acid.
Examples of the organic solvent to be used in the Friedel-Crafts reaction include tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, dichloroethane, acetonitrile, nitromethane and carbon disulfide. The present reaction may be carried out without a solvent if necessary.
The Friedel-Crafts reaction generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 100xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The Friedel-Crafts reaction is generally carried out for 30 minutes to 24 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the Friedel-Crafts reaction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
In the reduction, Clemmensen reaction or Wolff-Kishner reaction widely employed in the field of organic synthetic chemistry can be used, but the following reaction is especially useful for the present reaction.
Examples of the reagent to be used in the reduction include triethylsilane.
Examples of the organic solvent to be used in the reduction include trifluoroacetic acid, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, dichloroethane, acetonitrile and nitromethane.
The reduction generally proceeds at a temperature of from 0xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The reduction is generally carried out for 30 minutes to 10 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the reduction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the halogenating agent to be used in the halogenation of Compound (XLVIII) include hydrogen halide such as hydrochloric acid, hydrobromic acid or hydroiodic acid, phosphorous halide such as phosphorous chloride, phosphorous bromide, phosphorous pentachloride or phosphorous oxychloride, halogen such as chlorine, bromine or iodine, metal halide such as sodium bromide, sodium iodide or potassium iodide, thionyl chloride, carbon tetrachloride-triphenylphosphine, carbon tetrabromide-triphenylphosphine, N-chlorosuccinimide and N-bromosuccinimide. In the present reaction, iodine is preferably used in the presence of triphenylphosphine-imidazole or sodium iodide is preferably used. Moreover, the halogenation also can be carried out converting the hydroxyl into the corresponding methanesulfonyloxy by reacting with methanesulfonyl chloride, and then followed by reacting a halogenating agent such as sodium iodide.
Examples of the solvent to be used in the halogenation include water, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, methylene chloride, chloroform, dichloroethane, acetonitrile, benzene, toluene, xylene, acetone and 2-butanone.
The halogenation generally proceeds at a temperature of from 0xc2x0 C. to 100xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The halogenation is generally carried out for an hour to 12 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the halogenation is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Compound (XLVII) is halogenated and subjected to protection/deprotection, if necessary, to give a compound of the formula (L) [hereinafter referred to as Compound (L)]
wherein Hal, XA and Z are as defined above.
The halogenation of Compound (XLVII) is carried out the same as the halogenation of Compound (XLVIII).
[Method S]
Compound (II) wherein X is a straight-chain alkoxy having carbon atoms in the number of (pxe2x88x921) which may have 1 to 3 substituents selected from the group consisting of an alkyl, hydroxy, an alkoxy, an acyloxy, amino, an alkylamino, an acylamino, oxo, a haloalkyl, a halogen and a phenyl which may have substituents, and Lv is a halogen, can be produced according to the following method. Namely, a compound of the formula (LI) [hereinafter referred to as Compound (LI)]
wherein Y and Z are as defined above, when Y has a functional group (e.g. amino, hydroxy, oxo), the functional group may be protected if necessary; and Compound (XL) are condensed in the presence of a base to give a compound of the formula (LII) [hereinafter referred to as Compound (LII)]
wherein XA, Y and Z are as defined above, when XA has a functional group (e.g. amino, hydroxy, oxo), the functional group may be protected if necessary; which is halogenated and subjected to protection/deprotection, if necessary, to give a compound of the formula (LIII) [hereinafter referred to as Compound (LIII)]
wherein Hal, XA, Y and Z are as defined above.
Examples of the base to be used in the condensation include sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide, lithium hexamethyldisilazane, diisopropylethylamine and 1,8-diazabicyclo[4.3.0]undec-5-ene.
Examples of the organic solvent to be used in the condensation include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile.
The condensation generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 150xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The condensation is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the condensation is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the halogenating agent to be used in the halogenation of Compound (LII) include hydrogen halide such as hydrochloric acid, hydrobromic acid or hydroiodic acid, phosphorous halide such as phosphorous chloride, phosphorous bromide, phosphorous pentachloride or phosphorous oxychloride, halogen such as chlorine, bromine or iodine, metal halide such as sodium bromide, sodium iodide or potassium iodide, thionyl chloride, carbon tetrachloride-triphenylphosphine, carbon tetrabromide-triphenylphosphine, N-chlorosuccinimide and N-bromosuccinimide. In the present reaction, iodine is preferably used in the presence of triphenylphosphine-imidazole or sodium iodide is preferably used. Moreover, the halogenation also can be carried out converting the hydroxyl into the corresponding methanesulfonyloxy by reacting with methanesulfonyl chloride, and then followed by reacting a halogenating agent such as sodium iodide.
Examples of the solvent to be used in the halogenation include water, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, methylene chloride, chloroform, dichloroethane, acetonitrile, benzene, toluene, xylene, acetone and 2-butanone.
The halogenation generally proceeds at a temperature of from 0xc2x0 C. to 100xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The halogenation is generally carried out for an hour to 12 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the halogenation is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization chromatography or a method using an ion exchange resin.
[Method T]
Compound (I-5) is subjected to reduction and protection/deprotection, if necessary, to give a compound of the formula (I)-10) [hereinafter referred to as Compound (I-10)]
wherein Rj is hydrogen, an alkyl or an acyl and W, XA, Z, R1, R2, R3 and m are as defined above, and when W and XA have a functional group (e.g. amino, hydroxy, oxo), the functional group may be protected if necessary.
Examples of the reducing agent to be used in the reduction include sodium borohydride, lithium borohydride, lithium aluminum hydride, aluminum diisobutyl hydride, lithium aluminum hydride trimethoxy, lithium aluminum hydride tri-tert-butyl and diborane.
Examples of the organic solvent to be used in the reduction include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, acetone and methyl ethyl ketone.
The reduction generally proceeds at a temperature of from xe2x88x92100xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The reduction is generally carried out for 30 minutes to 10 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the reduction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
[Method U]
Compound (I-10) obtained in Method T is subjected to Mitsunobu reaction with a phthalimide or hydrogen azide [Synthesis, 1 (1981)] to give an each compound of the formula (LIV) or formula (LV) [hereinafter referred to as Compound (LIV) or Compound (LV)]
wherein W, XA, Z, R1, R2, R3 and m are as defined above, when W and XA have a functional group (e.g. amino, hydroxy, oxo), the functional group may be protected if necessary. Compound (LIV) is treated with a base or Compound (LV) is subjected to reduction, and the each compound obtained is subjected to protection/deprotection, if necessary, to give a compound of the formula (I-11) [hereinafter referred to as Compound (I-11)]
wherein R5 and R6 are the same or different and each is hydrogen, an alkyl or an acyl, and W, XA, Z, R1, R2, R3 and m are as defined above.
Examples of the reagent to be used in the Mitsunobu reaction include azodicarboxylic acid ester (e.g. ethyl azodicarboxylate)-triphenylphosphine.
The hydrogen azide to be used in the Mitsunobu reaction can be produced by treating metal azide such as sodium azide or lithium azide in sulfuric acid or treating trimethylsilylazide with methanol in a solvent such as tetrahydrofuran if necessary.
The Mitsunobu reaction generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 40xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The Mitsunobu reaction is generally carried out for an hour to 24 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the Mitsunobu reaction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the base to be used in the reaction of Compound (LIV) include hydrazine hydrate, methylhydrazine and phenylhydrazine.
Examples of the organic solvent to be used in the present reaction include methanol, ethanol, propanol, isopropyl alcohol and butanol.
The reaction generally proceeds at a temperature of from 50xc2x0 C. to the refluxing temperature of the solvent to be used and a lower or higher temperature than said temperature range may be selected on demand.
The present reaction is generally carried out for an hour to 10 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the present reaction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the reducing agent to be used in the reduction of Compound (LV) include metallic reducing reagent such as sodium borohydride, lithium borohydride or lithium aluminum hydride, transition metal such as Lindlar catalyst (palladium, calcium carbonate), palladium carbon, Raney nickel, platinum oxide, rhodium or rutenium for catalytic reduction.
Examples of the organic solvent to be used in the reduction of Compound (LV) include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, dioxane, acetone, ethyl acetate, acetic acid, benzene, toluene, xylene, dimethylformamide and dimethyl sulfoxide.
The reduction generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The reduction is generally carried out for an hour to 24 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the reduction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
[Method V]
In Compound (VII) wherein n is 2, the protecting group (P1) is removed selectively and the compound obtained is subjected to an alkaline treatment or treating by heating to give a compound of the formula (LVI) [hereinafter referred to as Compound (LVI)]
wherein X, Y, Z and Rd are as defined above; which is, in the presence of a base, subjected to alcoholysis to give a compound of the formula (LVII) [hereinafter referred to as Compound (LVII)]
wherein Rh is a lower alkyl such as methyl or ethyl, and X, Y and Z are as defined above. The ester compound obtained is subjected to reduction, and then oxidation if necessary to give a compound of the formula (LVIII) [hereinafter referred to as Compound (LVIII)]
wherein X, Y and Z are as defined above; which is condensed, in the presence of a base, with a compound of the formula (XLIV) wherein Ri is hydrogen, and subjected to protection/deprotection, if necessary, to give a compound of the formula (LIX) [hereinafter referred to as Compound (LIX)]
wherein X, Y and Z are as defined above; the double bond in the compound obtained is subjected to hydration and then the cyclic urethane thereof is hydrolyzed, and subjected to protection/deprotection, if necessary, to give a compound of the formula (I)-12) [hereinafter referred to as Compound (I-12)]
wherein R1, R2, R3, R4, X, Y and Z are as defined above.
Examples of the base to be used in the alcoholysis include sodium methoxide, sodium ethoxide, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[4.3.0]undec-5-ene.
Examples of the organic solvent to be used in the alcoholysis include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile.
After the alcoholysis is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the reducing agent to be used in the reduction of ester include diisobutyl aluminum hydride, lithium aluminum hydride, sodium borohydride and lithium borohydride. When the reduction isomer obtained is alcohol, as a method for oxidizing alcohol to aldehyde, Collins oxidation, Jones oxidation, PCC oxidation and Swern oxidation widely employed in the field of organic synthetic chemistry are useful.
Examples of the organic solvent to be used in the reduction include hexane, benzene, toluene, methylene chloride, methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether.
The reduction generally proceeds at a temperature of from xe2x88x9278xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The reduction is generally carried out for 30 minutes to 10 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the reduction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the base to be used in the condensation include sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, n-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium hexamethyldisilazane, diisopropylethylamine and 1,8-diazabicyclo[4.3.0]undec-5-ene.
Examples of the organic solvent to be used in the condensation include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile.
The condensation generally proceeds at a temperature of from xe2x88x9278xc2x0 C. to 100xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The condensation is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the condensation is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
The two steps reaction comprising hydroboration and then oxidation is especially useful for the hydration.
Examples of the reagent to be used in the hydroboration include diborane and 9-borabicyclo[3.3.1]nonane (9-BBN).
Examples of the organic solvent to be used in the hydroboration include tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, benzene, toluene, xylene, dioxane, methylene chloride, chloroform and dichloroethane.
The hydroboration generally proceeds at a temperature of from xe2x88x9278xc2x0 C. to 50xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The hydroboration is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
In the oxidation carried out in after-treatment of hydroboration, a peracid such as hydrogen peroxide is usually used and the reaction is carried out in an aqueous alkaline solution such as sodium hydroxide.
The oxidation generally proceeds at a temperature of from 0xc2x0 C. to 50xc2x0 C. and a lower or higher temperature than Maid temperature range may be selected on demand.
The hydroboration is generally carried out for 30 minutes to 24 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the two steps reaction of hydroboration and oxidation is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the base to be used in the hydrolysis include sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide.
Examples of the organic solvent to be used in the hydrolysis include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, ethylene glycol dimethyl ether, dimethylformamide and dimethyl sulfoxide, and a mixed solvent thereof with water can be used if necessary.
The hydrolysis generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The hydrolysis is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the hydrolysis is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
[Method W]
The compound of the formula [hereinafter referred to as Compound (LX)]
wherein Rh is as defined above, is subjected to carbonyl-protection, and the obtained carbonyl-protecting compound is reduced, then protected with a suitable hydroxy protecting reagent such as benzyl halide (benzyl chloride, benzyl bromide or benzyl iodide) and then subjected to carbonyl-deprotection to give the compound (LXI) 
wherein R is a hydroxy protecting group such as benzyl; which is subjected to addition with the compound of the formula [hereinafter referred to as Compound (LXII)]
wherein Met and Z are as defined above, to give the compound of the formula [hereinafter referred to as Compound (LXIII)]
wherein R and Z are defined above; which is subjected to Ritter reaction and then protection/deprotection, if necessary, to give the compound of the formula [hereinafter referred to as Compound (LXIV)]
wherein R1, R2, R3, R4 and Z are as defined above.
The carbonyl protecting reaction of Compound (LX) is carried out by a method known in the field of organic synthetic chemistry. The reaction is, for example, carried out by treating with ethylene glycol in the presence of acid catalyst such as p-toluenesulfonic acid in a solvent such as benzene, toluene, xylene, methylene chloride, chloroform or hexane.
The reaction generally proceeds at a temperature of from 0xc2x0 C. to the refluxing temperature of the solvent to be used and a lower or higher temperature than said temperature range may be selected on demand.
The reaction is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the reaction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the reducing agent in the reduction include metallic reducing reagent such as diborane, sodium borohydride, lithium borohydride or lithium aluminum hydride.
Examples of the organic solvent to be used in the reduction include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether.
The reduction generally proceeds at a temperature of from xe2x88x92100xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The reduction is generally carried out for 30 minutes to 10 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the reduction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the base to be used in the protection of hydroxy include sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride, lithium diisopropylamide, lithium hexamethyldisilazane, diisopropylethylamine and 1,8-diazabicyclo[4.3.0]undec-5-ene.
Examples of the organic solvent to be used in the protection include methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform, dichloroethane and acetonitrile.
The protection generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 150xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The protection is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the protection is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the organic solvent to be used in the addition with Compound (LXII) include tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform and dichloroethane.
The addition generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 100xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The addition is generally carried out for 30 minutes to 2 days and a longer or shorter reaction period than the indicated period may be selected on demand.
After the addition is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
Examples of the reagent to be used in the Ritter reaction of Compound (LXIII) include hydrogen cyanide, acetonitrile and benzonitrile.
Examples of the organic solvent to be used in the Ritter reaction include acetic acid, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, methylene chloride, chloroform and dichloroethane.
Examples of the acid catalyst to be used in the Ritter reaction include a strong acid such as sulfuric acid or trifluoroacetic acid.
The Ritter reaction generally proceeds at a temperature of from xe2x88x9220xc2x0 C. to 80xc2x0 C. and a lower or higher temperature than said temperature range may be selected on demand.
The Ritter reaction is generally carried out for 30 minutes to 24 hours and a longer or shorter reaction period than the indicated period may be selected on demand.
After the Ritter reaction is carried out under the above-mentioned conditions or after removing the protecting group on demand, the objective compound can be purified by a method known in the field of organic synthetic chemistry, such as solvent extraction, recrystallization, chromatography or a method using an ion exchange resin.
[Method X]
In Method W, the same method is carried out using the compound of the formula [hereinafter referred to as Compound (LXV)] instead of Compound (LX)
Wbxe2x80x94COCH2COORhxe2x80x83xe2x80x83(LXV)
wherein Wb is methyl or ethyl and Rh is as difined above, to give the compound of the formula [hereinafter referred to as Compound (LXVI)]
wherein Wb, R1, R2, RB and Z are as difined above.
[Method Y]
In Method W and X, the same method is carried out using the Compound (XXII) instead of Compound (LXII), to give the compound of the formula 
wherein R1, R2, R3, R4, Wb, Z, X and Y are as defined above.
The benzene compounds of the present invention, optically isomers thereof and salts thereof can be used for the prevention or treatment of various indications such as immunosuppression in organs or bone marrow transplantation, various autoimmune diseases or various allergy diseases. Namely, the compounds of the present invention have pharmacological activities such as immunosuppressive activity or antimicrobial activity and therefore are useful for the prevention or treatment of resistance to transplantation or transplantation rejection of organs or tissues (such as heart, kidney, liver, lung, bone marrow, cornea, pancreas, intestinum tenue, limb, muscle, nervus, fatty marrow, duodenum, skin or pancreatic islet cell etc., including xeno-transplantation), graft-versus-host diseases by bone marrow transplantation, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, nephrotic syndrome lupus, Hashimoto""s thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes mellitus, type II adult onset diabetes mellitus, uveitis, nephrotic syndrome, steroid-dependent and steroid-resistant nephrosis, palmoplantar pustulosis, allergic encephalomyelitis, glomerulonephritis, etc., and infectious diseases caused by pathogenic microorganisms.
The compounds of the present invention are useful for treating inflammatory, proliferative and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses such as psoriasis, psoriatic arthritis, atopic eczema (atopic dermatitis), contact dermatitis and further eczematous dermatitises, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, acne, alopecia areata, eosinophilic fasciitis, and atherosclerosis.
More particularly, the compounds of the present invention are useful in hair revitalizing, such as in the treatment of female or male pattern alopecia, or senile alopecia, by providing epilation prevention, hair germination, and/or a promotion of hair generation and hair growth.
The compounds of the present invention are further useful in the treatment of respiratory diseases, for example, sarcoidosis, fibroid lung, idiopathic interstitial pneumonia, and reversible obstructive airways disease, including conditions such as asthma, including bronchial asthma, infantile asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma, particularly chronic or inveterate asthma (for example late asthma and airway hyperreponsiveness), bronchitis and the like.
The compounds of the present invention may also be useful for treating hepatic injury associated with ischemia.
The compounds of the present invention are also indicated in certain eye diseases such as conjunctivitis, keratoconjunctivitis, keratitis, vernal conjunctivitis, uveitis associated with Beheet""s disease, herpetic keratitis, conical cornea, dystorphia epithelialis corneae, keratoleukoma, ocular pemphigus, Mooren""s ulcer, scleritis, Graves"" ophthalmopathy, severe intraocular inflammation and the like.
The compounds of the present invention are also useful for preventing or treating inflammation of mucosa or blood vessels (such as leukotriene B4-mediated diseases, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel disease, inflammatory bowel disease (e.g. Crohn""s disease and ulcerative colitis) necrotizing enterocolitis), or intestinal lesions associated with thermal burns.
Further, the compounds of the present invention are also useful for treating or preventing renal diseases including interstitial nephritis, Goodpasture""s syndrome, hemolytic uremic syndrome and diabetic nephropathy; nervous diseases selected from multiple myositis, Guillain-Barrxc3xa9 syndrome, Mxc3xa9nixc3xa8re""s disease and radiculopathy, endocrine diseases including hyperthyroidism and Basedow""s disease; hematic diseases including pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis and anerythroplasia; bone diseases including osteoporosis; respiratory diseases including sarcoidosis, fibroid lung and idiopathic interstitial pneumonia; skin diseases including dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T cell lymphoma; circulatory diseases including arteriosclerosis, aortitis, polyarteritis nodosa and myocardosis; collagen disease including scleroderma, Wegener""s granuloma and Sjxc3x6gren"" syndrome; adiposis; eosinophilic fasciitis; periodontal disease; nephrotic syndrome; hemolytic uremic syndrome; and muscular dystrophy.
Further, the compounds of the present invention are indicated in the treatment of diseases including intestinal inflammations or allergies such as Coeliac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn""s disease or ulcerative colitis; and food related allergic diseases which have symptomatic manifestation remote from the gastrointestinal tract, for example migraine, rhinitis and eczema.
The compounds of the present invention also have liver regenerating activity and/or activity in promoting hypertrophy and hyperplasia of hepatocytes. Therefore, they are useful for the treatment and prevention of hepatic diseases such as immunogenic diseases (e.g. chronic autoimmune liver diseases including autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial liver resection, acute liver necrosis (e.g. necrosis caused by toxins, viral hepatitis, shock or anoxia), B-virus hepatitis, non-A/non-B hepatitis and cirrhosis.
The compounds of the present invention are also indicated for use as antimicrobial agents, and thus may be used in the treatment of diseases caused by pathogenic microorganisms and the like.
Further, the compounds of the present invention can be used in the prevention or treatment of malignant rheumatoid arthritis, amyloidosis, fulminant hepatitis, Shy-Drager syndrome, pustular psoriasis, Behcet""s disease, systemic lupus erythematosus, endocrine opthalmopathy, progressive systemic sclerosis, mixed connective tissue disease, aortitis syndrome, Wegener""s gramulomatosis, active chronic hepatitis, Evans syndrome, pollinosis, idiopathic hypoparathyroidism, Addison disease (autoimmune adrenalitis), autoimmune orchitis, autoimmune oophoritis, cold hemagglutinin, paroxysmal cold hemoglobinuria, pernicious anemia, adult T cell leukemia, autoimmune atrophic gastritis, lupoid hepatitis, tubulointerstitial nephritis, membranous nephritis, amyotrophic lateral sclerosis, rheumatic fever, postmyocardial infarction syndrome and sympathetic ophthalmitis.
The compounds of the present invention have antifungal effect and are useful as a antifungal agent. Also, the compounds protected with a protecting group are useful as intermediates for the synthesis of the compounds having superior pharmacological actions.
When these compounds are used as pharmaceuticals, an effective amount thereof is generally admixed with carrier, excipient, diluent and so on and formulated into powders, capsules, tablets, injections, topical administration preparations or the like for the administration to patients. A lyophilized preparation may be produced by a method known per se.
While the dose of these compounds varies depending on disease, symptom, body weight, sex, age and so on, they may be administered, for example, to an adult daily by 0.01-10 mg (potency) in a single to several times divided doses when suppressing rejection in kidney transplantation.
Moreover, the compounds of the present invention can be used as a suppressant of rejection in organ or bone marrow transplantation in combination with other immunosuppressant(s), steroid(s) (prednisolone, methylprednisolone, dexamethasone, hydrocortisone and the like) or nonsteroidal anti-inflammatory agent. As the other immunosuppressant, preferred is particularly selected from azathiprine, brequinar sodium, deoxyspergualin, mizoribine, mycophenolate 2-morphorinoethyl, cyclosporin, rapamycin, tacrolimus monohydrate, leflunomide and OKT-3.